Diarrheal diseases have been recognized since ancient times as a major cause of morbidity and mortality. Such illnesses have continued to rank 1st or 2nd among infectious diseases in frequency and mortality, with a disproportionately heavy burden in infants and young children. Over the past two decades, rotaviruses have emerged as the single most important cause of severe diarrhea in infants and young children world-wide causing approximately one-third to one-half of these illnesses. Thus, the need for a rotavirus vaccine has received international endorsement. We have developed a rotavirus vaccine that contains 4 components in order to protect against the four epidemiologically important rotavirus serotypes. This vaccine is comprised of rhesus rotavirus (RRV) representing serotype 3 (the Jennerian approach) and three human rotavirus-RRV reassortants, each possessing ten RRV genes and a single human rotavirus gene that encodes VP7 (a major outer shell protein) that is responsible for serotype 1, 2 or 4 specificity (the modified Jennerian approach). Collaborative trials have been completed in over 10,000 infants and young children with single or multiple vaccine components with promising results in most but not all studies. However, in 4 major field trials with the quadrivalent vaccine, 3 in developed countries and one in a developing country setting, protective efficacy against severe diarrhea reached 80% or greater raising expectations that an effective rotavirus vaccine may become available in the not-too-distant future.